Burn injury initiates a series of pathophysiological changes. A progressive fall in left ventricular (LV) contractile function despite aggressive fluid resuscitation has been reported in both clinical and experimental studies of burn injury. However, the source(s) or the signaling pathways involved in burn-induced myocardial dysfunction remain largely unknown. Recent studies from our group indicated that gut-derived myocardial depressant factors carried in intestinal lymph trigger myocardial contractile depression. In addition, our preliminary studies demonstrated that the physiologically relevant concentrations of mesenteric lymph collected from rats receiving 40 % burn injury (burn lymph), but not lymph from sham-burned rats (control lymph), to ventricular myocytes isolated from healthy rats leads to a significant alterations in action potential duration associated with disturbed Ca2+homeostasis. In other preliminary work, we have found that burn lymph increases myocyte size, mitogen-activated protein kinases and cell death of cultured neonatal rat ventricular myocytes after 24 hrs incubation, suggesting a common mechanistic link between burn trauma and hypertrophic heart disease. In this proposal, we will capitalize on these discoveries and propose to further investigate the cellular and molecular mechanisms involved in burn-induced myocardial dysfunction and the roles of burn lymph in physiological and pathophysiological conditions. To begin understanding the cellular basis for altered myocardial function, this proposal focuses on cellular mechanisms important for myocardial Ca2+ homeostasis. Wehypothesize that 1)burn injury-inducedLV dysfunction issecondary to gut-derived factor(s) contained in mesenteric lymph (burn lymph), and 2)changes in ionic currents and Ca2"-cyclingproteins caused by burn lymph areinvolvedin burn-inducedLV dysfunction and ultimately to heart failure (HF). To test the hypothesis, this grant proposal also includes genomics and protein chemistry to elucidate valuable information in the heart after burn injury. This research is fundamental to our understanding of molecular mechanisms of burn-related myocardial dysfunction. A better understanding of molecular etiology and downstream mechanisms could lead to improved therapeutic measures to reduce the morbidity and mortality associated with burn injury. UMDNJ-New Jersey Medical School, Newark, NJ PHS 398 (Rev. 09/04) Page 2 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): Yatani, AtSUko, Ph.D. KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Yatani, Atusko,Ph.D. UMDNJ, NJMS, Dept. of Cell Principal Investigator Biology &Molecular Medicine Kaiser, Vicki,Ph.D. UMDNJ, NJMS, Dept. of Co-Investigator Surgery Shen, You-Tang, M.D. UMDNJ, NJMS, Dept. of Cell Co-Investigator Biology &Molecular Medicine Xu, Da-Zhong, M.D., Ph.D. UMDNJ, NJMS, Dept. of Co-Investigator Surgery OTHER SIGNIFICANT CONTRIBUTORS Name Deitch, Edwin A., M.D. Depre, Christophe, M.D., Ph.D. Vatner, Dorothy E.,M.D. Vatner, Stephen F., M.D. Organization Role on Project UMDNJ, NJMS, Dept. of Surgery Consultant UMDNJ, NJMS, Dept. of Cell Biology Consultant and Molecular Medicine UMDNJ, NJMS, Dept. of Cell Biology Consultant and Molecular Medicine UMDNJ, NJMS, Dept. of Cell Biology Consultant and Molecular Medicine Human Embryonic Stem Cells ^ No C] Yes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://Stemcells.nih.qov/reqistrv/index.asp. Use continuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line Disclosure Permission Statement. Applicable to SBIR/STTR Only. See SBIR/STTR instructions. Yes PHS 398 (Rev. 09/04) Page 3 Form Page 2-continued Number the following pages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, First, Middle): Yatani, AtSUko, Ph.D. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,